Medical database analysis of the association between kidney function and achievement of glycemic control in older Japanese adults with type 2 diabetes who started with oral antidiabetic drugs.

AIMS/INTRODUCTION: Despite the emergence of new drugs with novel mechanisms of action, treatment options for older people and those with chronic kidney disease are still limited. MATERIALS AND METHODS: Using a medical database compiled from Diagnostic Procedure Combination hospitals, we retrospectively analyzed treatment status, glycemic control and kidney function over 3 years after the first oral antidiabetic drugs in Japanese adults with type 2 diabetes who were aged ≥65 years. RESULTS: Among 5,434 study participants, 3,246 (59.7%) were men, the median age was 72.0 years, the baseline median hemoglobin A1c was 7.1% and the baseline median estimated glomerular filtration rate was 66.6 mL/min/1.73 m2. Treatment was intensified in 40.0% of people during the 3-year observation period, and the median time to the first treatment intensification was 198 days. Insulin was the most commonly used agent for treatment intensification (36.9%, 802/2,175). Hemoglobin A1c of <7.0% was achieved in 3,571 (65.7%) at 360 ± 90 days. Multivariable logistic regression analysis found that baseline age, hemoglobin A1c and estimated glomerular filtration rate were negatively associated with achieving hemoglobin A1c of <7.0% at 360 ± 90 days. CONCLUSIONS: In older Japanese adults with type 2 diabetes, those with a lower estimated glomerular filtration rate were more likely to achieve hemoglobin A1c of <7.0%. To safely manage blood glucose levels in older adults with chronic kidney disease, physicians should remain vigilant about the risk of iatrogenic hypoglycemia.

Prevalence, Incidence, and Clinical Characteristics of Thyroid Eye Disease in Japan.

Background: Although thyroid eye disease (TED) can impact social and psychological well-being, the epidemiological evidence of TED is lacking in Japan. Methods: Nationwide claims databases provided by JMDC Inc. and Medical Data Vision Co., Ltd. and national population statistics are used. Three TED definitions ranging from a strict definition only including a TED diagnosis to a broad definition including a TED diagnosis and considering ocular symptoms are considered. The proportion of patients by severity and disease activity are estimated based on definitions that would allow identification of those patients within the claims data. Results: The incidence rate per 100 000 person-years ranged from 7.3 to 11.1 for the strict and broad TED definitions, respectively. For fiscal year 2020 (April 2020 to March 2021) the prevalence rate ranged between 24.65 (strict TED) and 37.58 (broad TED) per 100 000 persons. These correspond to 25 383 and 38 697 patients for the strict and broad TED definitions, respectively. Regardless of the definition used, a predominance of female patients was observed, and the highest burden of the disease was seen in the age group of 35 to 59. Mild and inactive forms of TED were predominant (about 85% and 74%, respectively). Conclusion: The incidence and prevalence of TED in Japan were 7.3 to 11.1 per 100 000 person-years and 24.65 to 37.58 per 100 000 persons, respectively. The robust results of this database study add valuable real-world evidence on the incidence and prevalence of TED in Japan.

Prevalence and predictors of clinical inertia in patients with type 2 diabetes who were treated with a single oral antidiabetic drug.

AIMS/INTRODUCTION: Clinical inertia, defined as a failure of healthcare providers to initiate or intensify treatment when indicated, is one of the challenges in achieving glycemic targets in type 2 diabetes patients. MATERIALS AND METHODS: Using a Japanese medical database compiled from Diagnostic Procedure Combination hospitals, this retrospective study investigated clinical inertia in type 2 diabetes patients treated with a single oral antidiabetic drug. We analyzed predictors of clinical inertia, measured the time to treatment intensification, and monitored patients' glycemic control and renal function for 2 years. The index date was defined as the first date of hemoglobin A1c ≥7.0% during the 180 (±60) days after the first oral antidiabetic drug was prescribed. RESULTS: Clinical inertia was identified in 35.3% of patients. The median time to treatment intensification from the index date was 75.5 days. The proportion of patients achieving hemoglobin A1c <7.0% within 2 years was 33.8% with clinical inertia, and 47.9% without clinical inertia. Multivariate logistic regression analysis showed that Charlson Comorbidity Index score and an interval between visits of ≥6 weeks significantly increased the risk of developing clinical inertia, and hyperlipidemia and higher hemoglobin A1c at baseline significantly decreased the risk. CONCLUSIONS: This study showed that clinical inertia in type 2 diabetes patients treated with a single oral antidiabetic drug might have a lasting effect on long-term glycemic control. Our findings will inform clinicians of the characteristics of patients associated with clinical inertia and the importance of providing appropriate treatment under clinical practice guidelines.

Anti-inflammatory activity of bone morphogenetic protein signaling pathways in stomachs of mice.

BACKGROUND & AIMS: Bone morphogenetic protein (BMP)4 is a mesenchymal peptide that regulates cells of the gastric epithelium. We investigated whether BMP signaling pathways affect gastric inflammation after bacterial infection of mice. METHODS: We studied transgenic mice that express either the BMP inhibitor noggin or the ß- galactosidase gene under the control of a BMP-responsive element and BMP4(ßgal/+) mice. Gastric inflammation was induced by infection of mice with either Helicobacter pylori or Helicobacter felis. Eight to 12 weeks after inoculation, gastric tissue samples were collected and immunohistochemical, quantitative, reverse-transcription polymerase chain reaction and immunoblot analyses were performed. We used enzyme-linked immunosorbent assays to measure cytokine levels in supernatants from cultures of mouse splenocytes and dendritic cells, as well as from human gastric epithelial cells (AGS cell line). We also measured the effects of BMP-2, BMP-4, BMP-7, and the BMP inhibitor LDN-193189 on the expression of interleukin (IL)8 messenger RNA by AGS cells and primary cultures of canine parietal and mucus cells. The effect of BMP-4 on NFkB activation in parietal and AGS cells was examined by immunoblot and luciferase assays. RESULTS: Transgenic expression of noggin in mice increased H pylori- or H felis-induced inflammation and epithelial cell proliferation, accelerated the development of dysplasia, and increased expression of the signal transducer and activator of transcription 3 and activation-induced cytidine deaminase. BMP-4 was expressed in mesenchymal cells that expressed α-smooth muscle actin and activated BMP signaling pathways in the gastric epithelium. Neither BMP-4 expression nor BMP signaling were detected in immune cells of C57BL/6, BRE-ß-galactosidase, or BMP-4(ßgal/+) mice. Incubation of dendritic cells or splenocytes with BMP-4 did not affect lipopolysaccharide-stimulated production of cytokines. BMP-4, BMP-2, and BMP-7 inhibited basal and tumor necrosis factor α-stimulated expression of IL8 in canine gastric epithelial cells. LDN-193189 prevented BMP4-mediated inhibition of basal and tumor necrosis factor α-stimulated expression of IL8 in AGS cells. BMP-4 had no effect on TNFα-stimulated phosphorylation and degradation of IκBα, or on TNFα induction of a NFκß reporter gene. CONCLUSIONS: BMP signaling reduces inflammation and inhibits dysplastic changes in the gastric mucosa after infection of mice with H pylori or H felis.

Transumbilical Hidden-Scar High Anterior Resection for Sigmoid Colon Cancer Using GelPOINT® Through an Umbilical Zigzag Skin Incision.

Introduction: Hidden-scar surgery is a new method by which surgeons perform abdominal operations through one incision made in the folds of the patient's umbilicus. However, with a straight incision in the umbilicus, the maximal opening of the fascia is 2 cm. The 2-cm fascial opening is not enough to allow for the triangulation of instruments, the removal of specimens, and the performance of anastomosis, particularly during gastrectomy and colectomy. To overcome this problem, we developed an umbilical zigzag skin incision with a 6-cm opening of the fascia and peritoneum in collaboration with plastic surgeons and used Gelport® to maintain pneumoperitoneum, which resulted in a scarless wound.1 Plastic surgeons modified this technique from umbilicoplasties for umbilical deformities.2,3 We have performed gastrectomies, colectomies, cholecystectomies, and transabdominal preperitoneal hernia repairs using this method without any complications and have succeeded in hiding scars in the umbilicus. GelPOINT® is a newly developed device for minimally invasive surgery that provides a flexible, air-tight fulcrum to facilitate the triangulation of standard instrumentation. By offering an increased range of motion and maximum retraction and exposure, the GelPOINT platforms assure maximum versatility and access for a wide range of abdominal procedures. We report herein a video (559 seconds) describing a new method of transumbilical hidden-scar surgery using GelPOINT through an umbilical zigzag skin incision. Materials and Surgical Technique: A 64-year-old woman underwent laparoscopic sigmoidectomy for sigmoid colon cancer. The procedure was performed as previously described1; after marking a zigzag skin incision in the umbilical region, the skin was incised along this line. Then, a GelPOINT double-ring wound retractor was inserted through the incision, which enlarged the diameter of the fascial opening to 6 cm. The GelPOINT was latched to the wound retractor ring, and the pneumoperitoneum was then inflated using CO2. One additional port was inserted in the right-lower abdomen for safety. Laparoscopic high anterior resection with lymph node dissection was performed in the standard fashion. The specimen was easily extracted from the abdomen through the umbilical zigzag incision, and the double-staple technique was used for anastomosis without any complications. The wound in the umbilical region was virtually hidden in the bottom of the umbilicus after surgery. Results and Conclusion: We performed an umbilical zigzag skin incision technique using GelPOINT for laparoscopic high anterior resection without any complications. We consider that this zigzag skin incision technique is one way to lessen the technical difficulties of laparoscopic surgery, resulting in a hidden scar in the umbilicus. The authors have no conflicts of interest or financial ties to disclose. Runtime of video: 9 mins 19 secs.

Bone morphogenetic protein signaling regulates gastric epithelial cell development and proliferation in mice.

BACKGROUND & AIMS: We investigated the role of bone morphogenetic protein (BMP) signaling in the regulation of gastric epithelial cell growth and differentiation by generating transgenic mice that express the BMP inhibitor noggin in the stomach. METHODS: The promoter of the mouse H+/K+-ATPase ß-subunit gene, which is specifically expressed in parietal cells, was used to regulate expression of noggin in the gastric epithelium of mice. The transgenic mice were analyzed for noggin expression, tissue morphology, cellular composition of the gastric mucosa, gastric acid content, and plasma levels of gastrin. Tissues were analyzed by immunohistochemical, quantitative real-time polymerase chain reaction, immunoblot, microtitration, and radioimmunoassay analyses. RESULTS: In the stomachs of the transgenic mice, phosphorylation of Smad 1, 5, and 8 decreased, indicating inhibition of BMP signaling. Mucosa were of increased height, with dilated glands, cystic structures, reduced numbers of parietal cells, and increased numbers of cells that coexpressed intrinsic factor, trefoil factor 2, and Griffonia (Bandeiraea) simplicifolia lectin II, compared with wild-type mice. In the transgenic mice, levels of the H+/K+-ATPase α-subunit protein and messenger RNA were reduced, whereas those of intrinsic factor increased. The transgenic mice were hypochloridric and had an increased number of Ki67- and proliferating cell nuclear antigen-positive cells; increased levels of plasma gastrin; increased expression of transforming growth factor-α, amphiregulin, and gastrin; and activation of extracellular signal-regulated kinase 2. CONCLUSIONS: Inhibiting BMP signaling in the stomachs of mice by expression of noggin causes loss of parietal cells, development of transitional cells that express markers of mucus neck and zymogenic lineages, and activation of proliferation. BMPs are therefore important regulators of gastric epithelial cell homeostasis.

[A very elderly case of recurrent gastric cancer with peritoneal dissemination effectively treated by combination chemotherapy of docetaxel (DOC) and S-1].

We report a case of a 77-year-old man with gastric cancer of Borrmann type 3, pyloric stenosis and liver invasion. Distal gastrectomy with liver film resection was performed. Pathological staging was IV(sig, pT4, pN2, H0, P0, CY0, M0, ly3, v3). We recommended adjuvant chemotherapy but the patient refused. He was diagnosed with a recurrence of peritoneal dissemination 4 months after the operation. He received docetaxel(DOC)at a starting dose of 40 mg/m2 by iv infusion on day 1 and S- 1 at a full dose of 100 mg/body daily for two weeks every three weeks. After 5 cycles of this combination therapy, the gastric cancer with peritoneal dissemination completely disappeared. He was recognized to have grade 2 hematologic toxicity, hand foot syndrome and stomatitis, and all treatment-related toxicities were resolved. No re-growth of gastric cancer has been seen for 9 months with this chemotherapy.

CD47 regulation of epithelial cell spreading and migration, and its signal transduction.

CD47 is an integrin-associated penta-transmembrane protein that possesses an immunoglobulin-like domain in its extracellular region. We have now investigated the role of CD47 in the regulation of epithelial cell spreading and migration. CD47 is colocalized with E-cadherin at cell-cell adhesion sites of epithelial cells. A Ca2+ switch experiment showed that CD47 was endocytosed and then relocalized to cell-cell adhesion sites in a similar manner to E-cadherin. Such polarized localization of CD47 required the multiple spanning region of this protein. Forced expression of CD47 induced cell spreading with marked lamellipodium formation and resulted in both partial disruption of cell-cell adhesion and enhancement of the hepatocyte growth factor-stimulated scattering of Madin-Darby canine kidney cells. The CD47-induced cell spreading was blocked by inhibition of Src and mitogen-activated protein kinase kinase. Thus, these results suggest that CD47 participates in the regulation of cell-cell adhesion and cell migration through reorganization of the actin cytoskeleton in epithelial cells. This function of CD47 is mediated by the activation of Src and mitogen-activated protein kinase kinase.

Impact of brachial-ankle pulse wave velocity and ankle-brachial blood pressure index on mortality in hemodialysis patients.

BACKGROUND: Pulse wave velocity (PWV) and ankle-brachial blood pressure index (ABPI) are markers for atherosclerosis, and each predicts mortality in patients undergoing hemodialysis. However, there have been no studies in the past that compared head-to-head the clinical validity of these 2 parameters. Compared with conventional aortic PWV, brachial-ankle PWV (baPWV) is considered simple and thereby easily applicable to clinical use. METHODS: To clarify the relationship between baPWV and ABPI and assess their prognostic values, we analyzed 785 hemodialysis patients with a mean age of 60.2 +/- 12.5 (SD) years for whom ABPI and baPWV at baseline had been measured simultaneously and who were followed up for 33.8 +/- 10.8 months. RESULTS: Of 785 patients, 131 deaths were recorded. In Kaplan-Meier analysis, all-cause mortality was progressively and significantly greater from the lowest quartile of baPWV onward (log-rank test, 41.8; P < 0.001). However, in Cox proportional hazards analysis, the impact of baPWV was insignificant when ABPI was included as a covariate. ABPI maintained strong predictive power in this model. When patients who had advanced peripheral arterial occlusive disease (ABPI < 0.9) were excluded from analysis, patients with the highest quartile of baPWV had significantly increased hazard ratios of all-cause (hazard ratio, 4.08; 95% confidence interval, 1.46 to 11.43; P < 0.007) and cardiovascular (hazard ratio, 7.03; 95% confidence interval, 1.49 to 33.08; P < 0.014) mortality. The predictive power of baPWV in this population was independent from other covariates associated with atherosclerotic disorders. CONCLUSION: In a head-to-head comparison, ABPI, but not baPWV, showed strong power in predicting the mortality of hemodialysis patients. However, baPWV was useful to pick a high-risk population in patients with ABPI greater than 0.9. Thus, screening hemodialysis patients by means of baPWV and ABPI provides complementary information in identifying a high-risk population.

Relationship between expression of cyclin D1 and impaired liver regeneration observed in fibrotic or cirrhotic rats.

BACKGROUND AND AIM: The mechanisms responsible for impaired regenerative ability after hepatic resection observed in chronic liver disease are not fully understood. We have examined the relationships between an altered expression of cell cycle-related proteins in regenerating liver after partial hepatectomy and the impaired regenerative process observed in fibrotic and cirrhotic rats. METHODS: We performed 70% partial hepatectomy in both control and porcine serum-induced fibrotic rats, and 45% partial hepatectomy in thioacetamide-induced cirrhotic rats because of the high mortality associated with 70% partial hepatectomy. Liver regeneration was monitored by proliferating cell nuclear antigen labeling index and the expression of G1 regulatory cell cycle-related proteins was determined by immunoblot analysis. RESULTS: Compared with controls, hepatocyte DNA synthesis, and induction of cyclin D1 and p21(CIP1) proteins were delayed but not suppressed in porcine serum-induced fibrotic rats and markedly inhibited in thioacetamide-induced cirrhotic rats. p27(KIP1) protein levels were unaffected by partial hepatectomy and did not differ among all three groups. CONCLUSION: Two distinct rat models of liver fibrosis and cirrhosis showed markedly different proliferative responses after partial hepatectomy. The delay or failure of cyclin D1 induction, but not the increase of p21(CIP1) or p27(KIP1) might be responsible for their impaired liver regeneration.

Rabconnectin-3, a novel protein that binds both GDP/GTP exchange protein and GTPase-activating protein for Rab3 small G protein family.

Rab3A, a member of the Rab3 small G protein family, regulates Ca(2+)-dependent exocytosis of neurotransmitter. The cyclical activation and inactivation of Rab3A are essential for the Rab3A action in exocytosis. GDP-Rab3A is activated to GTP-Rab3A by Rab3 GDP/GTP exchange protein (Rab3 GEP), and GTP-Rab3A is inactivated to GDP-Rab3A by Rab3 GTPase-activating protein (Rab3 GAP). It remains unknown how or in which step of the multiple exocytosis steps these regulators are activated and inactivated. We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. The cDNA of rabconnectin-3 was cloned from a human cDNA library and its primary structure was determined. Human rabconnectin-3 consisted of 3,036 amino acids and showed a calculated M(r) of 339,753. It had 12 WD domains. Tissue and subcellular distribution analyses in rat indicated that rabconnectin-3 was abundantly expressed in the brain where it was enriched in the synaptic vesicle fraction. Immunofluorescence and immunoelectron microscopy revealed that rabconnectin-3 was concentrated on synaptic vesicles at synapses. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles.